6m1k

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'''Unreleased structure'''
 
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The entry 6m1k is ON HOLD until Paper Publication
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==USP7 in complex with a novel inhibitor==
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<StructureSection load='6m1k' size='340' side='right'caption='[[6m1k]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6m1k]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6M1K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6M1K FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.255&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EZF:methyl+4-[[4-[[3-[4-(aminomethyl)phenyl]-2-methyl-7-oxidanylidene-pyrazolo[4,3-d]pyrimidin-6-yl]methyl]-4-oxidanyl-piperidin-1-yl]methyl]-3-chloranyl-benzoate'>EZF</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6m1k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6m1k OCA], [https://pdbe.org/6m1k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6m1k RCSB], [https://www.ebi.ac.uk/pdbsum/6m1k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6m1k ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/UBP7_HUMAN UBP7_HUMAN] Hydrolase that deubiquitinates target proteins such as FOXO4, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN and DAXX. Together with DAXX, prevents MDM2 self-ubiquitination and enhances the E3 ligase activity of MDM2 towards p53/TP53, thereby promoting p53/TP53 ubiquitination and proteasomal degradation. Deubiquitinates p53/TP53 and MDM2 and strongly stabilizes p53/TP53 even in the presence of excess MDM2, and also induces p53/TP53-dependent cell growth repression and apoptosis. Deubiquitination of FOXO4 in presence of hydrogen peroxide is not dependent on p53/TP53 and inhibits FOXO4-induced transcriptional activity. In association with DAXX, is involved in the deubiquitination and translocation of PTEN from the nucleus to the cytoplasm, both processes that are counteracted by PML. Involved in cell proliferation during early embryonic development. Involved in transcription-coupled nucleotide excision repair (TC-NER) in response to UV damage: recruited to DNA damage sites following interaction with KIAA1530/UVSSA and promotes deubiquitination of ERCC6, preventing UV-induced degradation of ERCC6. Contributes to the overall stabilization and trans-activation capability of the herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110 during HSV-1 infection. Involved in maintenance of DNA methylation via its interaction with UHRF1 and DNMT1: acts by mediating deubiquitination of UHRF1 and DNMT1, preventing their degradation and promoting DNA methylation by DNMT1. Exhibits a preference towards 'Lys-48'-linked Ubiquitin chains.<ref>PMID:11923872</ref> <ref>PMID:14506283</ref> <ref>PMID:15053880</ref> <ref>PMID:16160161</ref> <ref>PMID:16964248</ref> <ref>PMID:18716620</ref> <ref>PMID:18590780</ref> <ref>PMID:20153724</ref> <ref>PMID:21745816</ref> <ref>PMID:22411829</ref> <ref>PMID:22689415</ref> <ref>PMID:22466611</ref> <ref>PMID:22466612</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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USP7 as a deubiquitinase plays important roles in regulating the stability of some oncoproteins including MDM2 and DNMT1, and thus represents a potential anticancer target. Through comparative analysis of USP7 co-crystal structures in complex with the reported piperidinol inhibitors, we noticed that the USP7 Phe409 sub-site might have good adaptability to the ligands. Based on this observation, 55 N-aromatic and N-benzyl piperidinol derivatives were designed, synthesized and biologically evaluated, among which compound L55 was identified as a highly selective and potent USP7 inhibitor (IC50 = 40.8 nM, KD = 78.3 nM). X-ray crystallographic studies revealed that L55 bound to USP7 with a new pose that was very different from the previously reported inhibitors. The results of cellular assays showed that L55 had strong antitumor activity against LNCaP (IC50 = 29.6 nM) and RS4; 11 (IC50 = 41.6 nM) cells, probably through inducing cell death and restricting G0/G1 and S phases. Moreover, L55 dose-dependently reduced the protein levels of MDM2 and DNMT1 and increased the protein levels of p53 and p21. These findings could have valuable implications for designing novel structural classes of USP7 inhibitors.
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Authors: Liu, S.J., Zhou, X.Y., Li, M.L., Sun, H.B., Wen, X.A.
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N-benzylpiperidinol derivatives as novel USP7 inhibitors: Structure-activity relationships and X-ray crystallographic studies.,Li M, Liu S, Chen H, Zhou X, Zhou J, Zhou S, Yuan H, Xu QL, Liu J, Cheng K, Sun H, Wang Y, Chen C, Wen X Eur J Med Chem. 2020 Aug 1;199:112279. doi: 10.1016/j.ejmech.2020.112279. Epub, 2020 May 5. PMID:32497973<ref>PMID:32497973</ref>
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Description: USP7 in complex with a novel inhibitor
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Sun, H.B]]
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<div class="pdbe-citations 6m1k" style="background-color:#fffaf0;"></div>
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[[Category: Zhou, X.Y]]
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== References ==
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[[Category: Wen, X.A]]
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<references/>
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[[Category: Liu, S.J]]
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__TOC__
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[[Category: Li, M.L]]
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Li ML]]
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[[Category: Liu SJ]]
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[[Category: Sun HB]]
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[[Category: Wen XA]]
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[[Category: Zhou XY]]

Current revision

USP7 in complex with a novel inhibitor

PDB ID 6m1k

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